Expression of hypoxia-inducible factor-1alpha and cell cycle proteins in invasive breast cancer are estrogen receptor related.
Expression of hypoxia-inducible factor-1alpha and cell cycle proteins in invasive breast cancer are estrogen receptor related.
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DOI：
10.1186/bcr813
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
van der Wall E
中科院分区：
文献类型：
--
作者：
Bos R;van Diest PJ;van der Groep P;Shvarts A;Greijer AE;van der Wall E
转录因子低氧诱导因子-1(HIF-1)是细胞对低氧反应的关键调节因子。以往的研究表明，其亚基HIF-1α作为HIF-1活性的替代物，在乳腺癌发生过程中浓度升高，并可独立预测乳腺癌的预后。在癌变过程中，细胞周期逐渐失控，增殖率是乳腺癌的一个强有力的预后因素。在这项研究中，我们对缺氧诱导因子-1、α和细胞周期相关蛋白之间的关系进行了详细的评估。采用免疫组织化学方法检测了雌激素受体(ER)、血管内皮生长因子、ER、HER-2/neu、Ki-67、细胞周期蛋白A、细胞周期蛋白D1、p21、P53和Bcl2在乳腺癌组织中的表达。高浓度(5%或更高)的HIF-1α与细胞增殖呈正相关，与Ki-67(P<；0.001)和晚期S-G2期蛋白Cyclin A(P<；0.001)呈正相关，而与G1期蛋白Cyclin D1无相关性。高水平的HIF-1α表达与P53阳性表达(P<；0.001)和Bcl2表达缺失(P=0.013)密切相关。未发现p21与HIF-1α之间存在相关性(P=0.105)。而ER阳性肿瘤亚组中HIF-1α与p21表达呈正相关(P=0.023)，而HIF-1α与细胞增殖无关。低氧诱导因子-1α的过度表达与增殖增加有关，这可能解释了浸润性乳腺癌中低氧诱导因子-1α浓度升高对预后的不利影响。在ER阳性的肿瘤中，HIF-1α与p21相关，但不抑制增殖。这表明进一步的功能分析对于揭示HIF-1在细胞周期晚期进程中的作用以及HIF-1、p21和ER之间的联系具有重要意义。
The transcription factor hypoxia-inducible factor-1 (HIF-1) is a key regulator of the cellular response to hypoxia. Previous studies showed that concentrations of its subunit HIF-1α, as a surrogate for HIF-1 activity, are increased during breast carcinogenesis and can independently predict prognosis in breast cancer. During carcinogenesis, the cell cycle is progressively deregulated, and proliferation rate is a strong prognostic factor in breast cancer. In this study we undertook a detailed evaluation of the relationships between HIF-1α and cell cycle-associated proteins. In a representative estrogen receptor (ER) group of 150 breast cancers, the expression of HIF-1α, vascular endothelial growth factor, the ER, HER-2/neu, Ki-67, cyclin A, cyclin D1, p21, p53, and Bcl-2 was investigated by immunohistochemistry. High concentrations (5% or more) of HIF-1α were associated with increased proliferation as shown by positive correlations with Ki-67 (P < 0.001) and the late S–G2-phase protein cyclin A (P < 0.001), but not with the G1-phase protein cyclin D1. High HIF-1α concentrations were also strongly associated with p53 positivity (P < 0.001) and loss of Bcl-2 expression (P = 0.013). No association was found between p21 and HIF-1α (P = 0.105) in the whole group of patients. However, the subgroup of ER-positive cancers was characterized by a strong positive association between HIF-1α and p21 (P = 0.023), and HIF-1α lacked any relation with proliferation. HIF-1α overexpression is associated with increased proliferation, which might explain the adverse prognostic impact of increased concentrations of HIF-1α in invasive breast cancer. In ER-positive tumors, HIF-1α is associated with p21 but not against proliferation. This shows the importance of further functional analysis to unravel the role of HIF-1 in late cell cycle progression, and the link between HIF-1, p21, and ER.
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影响因子：
8.8
作者：
Michalides, R;van Tinteren, H;Balkenende, A;Vermorken, J B;Benraadt, J;Huldij, J;van Diest, P
通讯作者：
van Diest, P
影响因子：
4.8
作者：
Blagosklonny, MV;An, WG;Neckers, L
通讯作者：
Neckers, L
影响因子：
64.8
作者：
Maxwell, PH;Wiesener, MS;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
5.3
作者：
Goda, N;Ryan, HE;Johnson, RS
通讯作者：
Johnson, RS
DOI：
10.1136/mp.52.2.78
发表时间：
1999-04-01
期刊：
JOURNAL OF CLINICAL PATHOLOGY-MOLECULAR PATHOLOGY
影响因子：
--
作者：
de Jong, JS;van Diest, PJ;Baak, JPA
通讯作者：
Baak, JPA